The present invention relates to phenylpiperazine derivatives which have excellent xcex11-adrenoceptor blocking activity and are useful as medicaments; and to a process for producing the same.
A blocking agent against an xcex11-adrenoceptor, which dilates blood vessels or reduces resistance in the blood vessels, is known to be a preventive and therapeutic drug for hypertension such as essential hypertension or renal hypertension, congestive heart failure, myocardial ischemia, arrhythmia, and angina pectoris. Many compounds have been reported to serve as such a blocking agent. Moreover, an xcex11-adrenoceptor has been found to participate to a considerable degree in constriction of the urinary bladder neck (J. Urol., 134, 396 (1985)) and therefore, the blocking agent against the receptor has become of interest as a pharmaceutical capable of selectively treating urinary obstruction, pollakiuria, and other symptoms caused by benign prostatic hyperplasia (BPH). For example, prazosin hydrochloride and urapidil (British Patent No. 1156973, German Patent No. 1942405, WO89/12634, WO90/03972) have been used as pharmaceuticals for treatment of hypertension or urinary obstruction caused by BPH, and tamsulosin hydrochloride has been used as a pharmaceutical for treatment of urinary obstruction caused by BPH (Japanese Patent Application Laid-Open (Kokai) No. 110665/1981).
However, conventional blocking agents against an xcex11-adrenoreceptor do not necessarily exhibit sufficient effect for prevention and treatment of the above-described symptoms, and it is known that side effects such as orthostatic hypotension and loss of consciousness may result. In order to overcome these drawbacks, development of new drugs has still been demanded.
The present inventors have found that specific N-phenyl-Nxe2x80x2-phenylpropylpiperazine derivatives exhibit excellent xcex11-adrenoreceptor blocking activity and thus are useful as medicaments. The present invention has been achieved on the basis of this finding.
Accordingly, the present invention provides an N-phenyl-Nxe2x80x2-phenylpropylpiperazine derivative represented by formula (1): 
(wherein R1 represents a lower alkyl group; R2 represents a lower alkoxy group; and R3 represents a cyano group, a carboxyl group, or an indolecarbonyl group) or a salt thereof, as well as a process for producing the derivative or the salt thereof.
The present invention also provides a medicament which comprises as an active component an N-phenyl-Nxe2x80x2-phenylpropylpiperazine derivative represented by formula (1) or a salt thereof.
The present invention also provides a blocking agent against an xcex11-adrenoceptor, which blocking agent comprises as an active component an N-phenyl-Nxe2x80x2-phenylpropylpiperazine derivative represented by formula (1) or a salt thereof.
Further, the present invention provides a pharmaceutical composition which contains an N-phenyl-Nxe2x80x2-phenylpropylpiperazine derivative represented by formula (1) or a salt thereof and a pharmaceutically acceptable carrier.
Further, the present invention provides use of an N-phenyl-Nxe2x80x2-phenylpropylpiperazine derivative represented by formula (1) or a salt thereof as medicaments.
Furthermore, the present invention provides a treatment method for hypertension, congestive heart failure, myocardinal ischemia, arrhythmia, angina pectoris, or urinary obstruction and pollakiuria caused by BPH, characterized by administration of an N-phenyl-Nxe2x80x2-phenylpropylpiperazine derivative represented by formula (1) or a salt thereof.
WO95/26955 and WO99/03831, which have been filed by the present inventors, describe that an indole butyrate derivative has xcex11-adrenoceptor blocking activity, but are silent about the activity of the compound of formula (1).
In the present invention, the term xe2x80x9clowerxe2x80x9d refers to the number of carbon atoms being 1 to 6 in a linear, branched, or cyclic carbon-containing group.
Accordingly, the term xe2x80x9ca lower alkyl groupxe2x80x9d refers to a C1-C6 linear, branched, or cyclic alkyl group. Specific examples of such alkyl groups include methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, pentyl, 1-methylbutyl, 2-methylbutyl, isopentyl, tert-pentyl, 1,2-dimethylpropyl, neopentyl, 1-ethylpropyl, cyclopentyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, isohexyl, 1-ethylbutyl, 2-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-methyl-1-ethylpropyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, and cyclohexyl. Among these, C1-C4 linear or branched alkyl groups are preferred and a methyl group is most preferred.
The term xe2x80x9clower alkoxy groupxe2x80x9d refers to a C1-C6 linear, branched, or cyclic alkoxy group. Specific examples of such alkoxy groups include methoxy, ethoxy, propoxy, cyclopropoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, cyclobutoxy, pentyloxy, 1-methylbutoxy, 2-methylbutoxy, isopentyloxy, tert-pentyloxy, 1,2-dimethylpropoxy, neopentyloxy, 1-ethylpropoxy, cyclopentyloxy, hexyloxy, 1-methylpentyloxy, 2-methylpentyloxy, 3-methylpentyloxy, isohexyloxy, 1-ethylbutoxy, 2-ethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-methyl-1-ethylpropoxy, 1-ethyl-2-methylpropoxy, 1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy, and cyclohexyloxy. Among these, C1-C4 linear or branched alkoxy groups are preferred and a methoxy group is most preferred.
In the present invention, the term xe2x80x9cindolecarbonyl groupxe2x80x9d refers to a carbonyl group to which indole is bonded at one end. Specific examples of such indolecarbonyl groups include (indol-1-yl)carbonyl, (indol-2-yl)carbonyl, (indol-3-yl)carbonyl, (indol-4-yl)carbonyl, (indol-5-yl)carbonyl, (indol-6-yl)carbonyl, and (indol-7-yl)carbonyl. Among these, an (indol-3-yl)carbonyl group is most preferred.
In formula (1), R1 is preferably a methyl group and R2 is preferably a methoxy group. R3 is preferably a cyano group, a carboxyl group, or an (indol-3-yl)carbonyl group and most preferably a cyano group or a carboxyl group.
The compound (1) of the present invention forms a salt with an acid or a base. Examples of salts formed with an acid include salts formed with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; and with acidic amino acids such as aspartic acid and glutamic acid. Examples of salts formed with a base include salts formed with inorganic bases such as sodium, potassium, magnesium, calcium, aluminum, and zinc; and ammonium salts.
The present invention encompasses a variety of solvates or crystal polymorphisms of the compound (1) and further, encompasses racemic modifications and R- and S-stereoisomers as well as optically active substances of the compound (1).
The compound (1) of the present invention may be produced according to the following reaction scheme. 
(wherein R1 and R2 are the same as described above.)
4xe2x80x2-Lower alkyl-3-chloropropiophenone (2) which has been prepared according to a known method is reduced by use of a borohydride such as sodium borohydride to thereby yield 3-chloro-1-(4-alkylphenyl)-1-propanol (3). The reaction may be carried out in an alcoholic solvent such as methanol or ethanol, under cooled conditions, at room temperature, under warm conditions, or with heat. The obtained 3-chloro-1-(4-alkylphenyl)-1-propanol (3) can be divided into isomers including a variety of optical isomers and R- and S-isomers by optical resolution using an optical resolving agent such as optically active mandelic acid, tartaric acid, dibenzoyltartaric acid, or di(p-toluoyl)tartaric acid.
When (R)-5,5-diphenyl-2-methyl-3,4-propano-1,3,2-oxazaborolidine and a borane-diethylaniline complex are added to compound (2) for reaction therebetween, an S-isomer of 3-chloro-1-(4-methylphenyl)-1-propanol (3) can be produced. Similarly, (S)-5,5-diphenyl-2-methyl-3,4-propano-1,3,2-oxazaborolidine and a borane-diethylaniline complex are added to compound (2), and the mixture is allowed to react to thereby obtain an R-isomer of 3-chloro-1-(4-methylphenyl)-1-propanol (3). By use of the R-isomer and the S-isomer in each of the following reactions, an R-isomer and an S-isomer of compound (1) of the present invention can be produced. In the above-described reduction, sodium borohydride, dimethyl sulfate, and N,N-diethylaniline can be added instead of a borane-diethylaniline complex.
When a 1-(2-lower alkoxyphenyl)piperazine derivative (4), potassium iodide, and a base are added to compound (3) and the mixture is allowed to react, N-(3-hydroxy-3-phenylpropyl)piperazine derivatives (5) can be produced. Examples of the base include metal carbonates such as potassium carbonate and sodium carbonate; trialkyl amines such as triethylamine and diisopropylethylamine; and pyridines such as pyridine, lutidine, and 4-dimethylaminopyridine. The reaction is usually carried out in a solvent which does not affect the reaction, such as N,N-dimethylformamide, dimethylsulfoxide, acetone, or methylene chloride. The reaction may be carried out at room temperature, under warm conditions, or with heat.
An N-(3-hydroxy-3-phenylpropyl)piperazine derivative (5) is reacted with p-fluorobenzonitrile to thereby obtain compound (1a) of the present invention in which R3 is a cyano group. The reaction is usually carried out in the presence of a base such as sodium hydroxide, potassium hydroxide, potassium tert-butoxide, or sodium hydride; and in the presence or in the absence of a solvent which does not affect the reaction, such as N,N-dimethylformamide, dimethylsulfoxide, or tetrahydrofuran. The reaction may be carried out under cooled conditions, at room temperature, under warm conditions, or with heat.
Hydrolysis of the compound (1a) of the present invention in which R3 is a cyano group provides compound (1b) of the present invention in which R3 is a carboxylic group. The reaction is usually carried out in the presence of a base such as potassium hydroxide or sodium hydroxide and in a solvent such as methanol, ethanol, or tetrahydrofuran, or in a mixed solvent of one of the above solvent and water. The reaction is carried out under warm conditions, with heat, or under reflux with heat.
The compound (1b) of the present invention in which R3 is a carboxylic group is reacted with a halogenating agent such as thionyl chloride, oxalyl chloride, phosphorus trichloride, or phosphorus pentachloride to thereby activate the carboxylic group of the compound (1b) and further, reacted with a separately-prepared reaction product between indole and an organometallic compound, to thereby obtain compound (1c) of the present invention in which R3 is an indolecarbonyl group. The activation reaction of the carboxylic group of the compound (1b) may be carried out in the presence or in the absence of a solvent which does not affect the reaction, for example, a halogen-containing solvent such as methylene chloride and chloroform. The reaction may be carried out at room temperature, under warm conditions, or with heat. In the preparation of the reaction product between indole and an organometallic compound, there is employed a solvent which does not affect the reaction, for example, a halogen-containing solvent such as methylene chloride, chloroform, or 1,2-dichloroethane; ether such as diethyl ether, tetrahydrofuran, or dioxane; and benzene such as toluene or xylene. Examples of the organometallic compound include organic lithium compounds, organic aluminum compounds, organic zinc compounds, and organic magnesium compounds. Specific examples of organic lithium compounds include methyllithium and butyllithium; specific examples of organic aluminum compounds include trimethylaluminum and triethylaluminum; specific examples of organic zinc compounds include dimethylzinc and diethylzinc; and specific examples of organic magnesium compounds include methylmagnesium chloride, ethylmagnesium chloride, methylmagnesium bromide, ethylmagnesium bromide, methylmagnesium iodide, and ethylmagnesium iodide. The reaction may be carried out in the presence or in the absence of a zinc compound. Preferably, the reaction is carried out in the presence of a zinc compound and examples of the zinc compound include zinc chloride, zinc bromide, and zinc iodide. The reaction may be carried out under a cooled condition, at room temperature, under warm conditions, or with heat.
N-Phenyl-Nxe2x80x2-phenylpropylpiperazine derivative (1) obtained in the present invention may be converted to a salt with an acid or a base according to a customary method.
N-Phenyl-Nxe2x80x2-phenylpropylpiperazine derivative (1) and the salts thereof obtained in the present invention encompass a variety of solvates and crystal polymorphisms. Through suitable selection of raw materials, asymmetric reduction, and optical resolution using an optical resolving agent such as optically active mandelic acid, tartaric acid, dibenzoyltartaric acid, or di(p-toluoyl)tartaric acid, there can be produced different racemic modifications, a variety of optical isomers and R- and S-isomers.
The thus-obtained compound (1) of the present invention has excellent xcex11-adrenoceptor blocking activity and high safety. Therefore, the compound is useful as a preventive and therapeutic agent for hypertension, congestive heart failure, myocardinal ischemia, arrhythmia, angina pectoris, and urinary obstruction and pollakiuria caused by BPH.
The compound (1) of the present invention can be formed into a pharmaceutical composition for, for example, oral administration or parenteral administration, through formulation together with a pharmaceutically acceptable carrier. For oral administration, the compound (1) may be formed into tablets, powders, granules, or capsules through combination with suitable additives including excipients such as lactose, mannitol, corn starch, and crystalline cellulose; binders such as cellulose derivatives, gum arabic, and gelatin; disintegrators such as carboxymethylcellulose-Ca; and lubricants such as talc and magnesium stearate. The resultant solid preparations may be formed into enteric preparations by use of a coating agent such as hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, cellulose acetate phthalate, or a methacrylate copolymer. For parenteral administration, the compound (1) may be formed into injection liquids through combination with, for example, water, ethanol, glycerin, and customary surfactants; or into suppositories through combination with a suppository base.
The dose may vary in accordance with age, body weight, symptom, therapeutic effect, manner of administration, and administration period. Generally, in the case of oral administration, compound (1) of the present invention is administered in an amount of 1-2000 mg/day, preferably 10-300 mg/day, at a single dose or 2-3 divided doses per day.